1. Field of the Invention
The present invention relates to an interface (skin contactor or patch) which is useful for transdermal or percutaneous drug delivery by means of iontophoresis.
2. Description of the Related Art
Iontophoresis is a system for promoting or accelerating transdermal absorption (endermic absorption) with the use of electricity. The principle of such iontophoresis basically resides in promoting or enhancing transmittance of a drug molecule through a skin barrier due to, in an electric field between an anode and a cathode produced by an electric current, moving force of a positively charged molecule from the anode to the cathode, and a moving force of a negatively charged molecule from the cathode to the anode [see Journal of Controlled Release, 18, 213-220 (1992); Advanced Drug Delivery Review, 9, 119 (1992); and Pharmaceutical Research, 3, 318-326 (1986)].
Recent advances of synthetic technologies and genetic engineering insure pure and mass production of a naturally-occurring peptide or protein, or a peptide or protein in which the amino acid composition of the naturally-occurring peptide or protein is changed, or a chemically-modified derivative thereof. Thus, applications of these peptides or proteins for drugs or medicaments have been expected. On the other hand, a strict control of administration (dosage) of these peptides or proteins, which exhibit various physiological activities in an extremely small amount, is required for exhibition of the maximum drug effect and minimizing a side effect or adverse reaction in a specific disease.
Further, such physiologically active peptide or protein is generally decomposed by a digestive fluid or juice in a gastrointestinal tract (digestive tract) or hydrolyzed by a hydrolase present in the digestive tract wall, and hence absorption efficacy of the peptide or protein can hardly be improved with effectiveness. Therefore, for expecting a sufficient drug effect, the physiologically active peptide or protein is usually administered not orally but via an injection. Administration as an injectable preparation, however, causes great pain to a patient to be administered and burdens him with a heavy load since such injectable preparation can not be administered by himself.
In the field of pharmaceutical preparation, the iontophoresis has been intensively researched as a new drug delivery system. That is, use of the iontophoresis provides an administration of a drug, which has been administered as an injectable preparation, by a patient himself, and hence ensures expanded possibility of applications as therapy at home. Further, control of drug absorption time can be effected by a precise control or regulation of electric current or voltage application time. In particular, when the iontophoresis is applied to a supplemental therapy (treatment) of an endogenous compound in consideration of circadian rhythm of a living body, more effective therapy with it is expected to be realized.
In an administration system using the iontophoresis having such advantages, use is generally made of an electrode for applying an electric current by means of a direct-current electric power unit, a drug-holder (an interface as a skin contact or patch) which is conductible to the electrode and capable of making contact with the skin, and a reference electrode. As an interface, there have been reported an electrically nonconductive interface composed of an organic drug-supporting layer (e.g. a drug-supporting layer comprising a paper material, a woven or nonwoven fabric and other fabric material, a fibrous material, a synthetic resin continuous foam or water-absorbable resin and other sponge or porous body), and an electrically nonconductive interface comprising an inorganic support (e.g. a ceramic porous body, or a ceramic having a porous or capillary structure).
However, when a drug is supported on these drug-support by means of coating or impregnation, or supported in semi-dry or dry conditions, satisfactorily sufficient amount of transdermal drug absorption can not be expected. Accordingly, the bioavailability of the drug can hardly be improved. The reason of such low amount of transdermal absorption of the drug may be considered that the drug such as a physiologically active peptide or protein is adsorbed to the drug-support with a decreased bioavailability of the drug.
Japanese Patent Application Laid-open No. 16535/1994 (JP-A-6-16535) proposes the use of an interface (skin contactor) for iontophoresis as produced by coating a porous or capillary structure composed of an electrically nonconductive material with a high molecular weight protein such as a bovine serum albumin, a human serum albumin or gelatin for inhibiting the adsorption of a drug and hence ensuring effective improvement of transdermal absorptivity with a small amount of the drug. This literature describes that a nylon porous body (e.g. Biodyne) is preferable as a porous or capillary structure.
In the above interface, however, effective dose of the drug is remarkably decreased with elapse of time and hence effective absorption of the drug can hardly be expected. It is probably because of the adsorption of the drug to the structure as a base material of the interface and poor drug releasability by means of the iontophoresis. Therefore, effective and precise transdermal drug administration with high reproducibility and high bioavailability can,hardly be expected. That is, in the above interface, it is difficult to hold or support a physiologically active peptide or protein with a high retention and to administer them transdermally with a high bioavailability.
It is, therefore, an object of the present invention to provide an interface (skin contact) for iontophoresis which ensures effective and precise transdermal drug delivery with high bioavailability and high reproducibility.
It is another object of the invention to provide an interface for iontophoresis which inhibits the decrease of a retention amount of an effective drug and provides high releasability and effective transdermal delivery of the drug.
A further object of the invention is to provide an interface for iontophoresis which ensures improved or enhanced releasability and bioavailability of a physiologically active peptide or protein.
It is a yet another object of the invention to provide a method for promoting transdermal absorption of a drug with the use of the interface.
The inventors of the present invention made intensive investigations to accomplish the above-mentioned objects, and found that an arrangement of a membrane having a hydrophilic property and a low adsorptivity for a peptide or protein in a side or surface to be made contact with a skin ensures rapid release of a drug after contact with a dissolution liquid when it is a physiologically active peptide or protein and provides transdermal drug delivery with an extremely high bioavailability and excellent reproducibility. The invention has been accomplished on the basis of the above findings and further investigations.
Thus, (1) the interface for iontophoresis of the invention is provided with a membrane having a low adsorptivity for a protein including peptide (hereinafter referred to briefly as protein). In the interface for iontophoresis, (2) the adsorptivity for a protein of the membrane may be 0 to about 10 xcexcg per 1 cm2, (3) the thickness of the membrane may be about 10 to 200 xcexcm, and (4) the porosity of the membrane may be about 60 to 90%. (5) The membrane includes membranes of hydrophilized fluororesins, hydrophilized cellulose derivatives, hydrophilized polysulfones and others.
It should be understood that, in the present specification, the term xe2x80x9clow adsorptivity for a proteinxe2x80x9d means, for example, that adsorptivity for a peptide fragment of the N-terminus (1xe2x86x9234-position) of a human PTH (hereinafter briefly referred to as xe2x80x9chPTH (1xe2x86x9234)xe2x80x9d) is not greater than 10 xcexcg/cm2.